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Genes 2017, 8(10), 253; doi:10.3390/genes8100253

Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene

1
Unidade de Genética Molecular, Centro de Genética Médica Dr. Jacinto Magalhães, Centro Hospitalar do Porto, 4050-106 Porto, Portugal
2
Unidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal
3
Serviço de Neurofisiologia, Departamento de Neurociências, Centro Hospitalar do Porto, 4099-001 Porto, Portugal
4
Unidade de Neuropatologia, Centro Hospitalar do Porto, 4099-001 Porto, Portugal
5
Departamento de Microscopia, Laboratório de Biologia Celular, Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal
6
Centro de Genética da Reprodução Prof. Alberto Barros, 4050-313 Porto, Portugal
7
UCIBIO/REQUIMTE, Departamento de Ciências Biológicas, Laboratório de Bioquímica, Faculdade de Farmácia, Universidade do Porto, 4050-313 Porto, Portugal
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Josyf C. Mychaleckyj
Received: 16 August 2017 / Revised: 15 September 2017 / Accepted: 19 September 2017 / Published: 3 October 2017
(This article belongs to the Section Human Genomics and Genetic Diseases)
View Full-Text   |   Download PDF [2198 KB, uploaded 10 October 2017]   |  

Abstract

A broad mutational spectrum in the dystrophin (DMD) gene, from large deletions/duplications to point mutations, causes Duchenne/Becker muscular dystrophy (D/BMD). Comprehensive genotyping is particularly relevant considering the mutation-centered therapies for dystrophinopathies. We report the genetic characterization of a patient with disease onset at age 13 years, elevated creatine kinase levels and reduced dystrophin labeling, where multiplex-ligation probe amplification (MLPA) and genomic sequencing failed to detect pathogenic variants. Bioinformatic, transcriptomic (real time PCR, RT-PCR), and genomic approaches (Southern blot, long-range PCR, and single molecule real-time sequencing) were used to characterize the mutation. An aberrant transcript was identified, containing a 103-nucleotide insertion between exons 51 and 52, with no similarity with the DMD gene. This corresponded to the partial exonization of a long interspersed nuclear element (LINE-1), disrupting the open reading frame. Further characterization identified a complete LINE-1 (~6 kb with typical hallmarks) deeply inserted in intron 51. Haplotyping and segregation analysis demonstrated that the mutation had a de novo origin. Besides underscoring the importance of mRNA studies in genetically unsolved cases, this is the first report of a disease-causing fully intronic LINE-1 element in DMD, adding to the diversity of mutational events that give rise to D/BMD. View Full-Text
Keywords: Becker muscular dystrophy; cDNA; DMD; Dystrophin; LINE-1 Becker muscular dystrophy; cDNA; DMD; Dystrophin; LINE-1
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Gonçalves, A.; Oliveira, J.; Coelho, T.; Taipa, R.; Melo-Pires, M.; Sousa, M.; Santos, R. Exonization of an Intronic LINE-1 Element Causing Becker Muscular Dystrophy as a Novel Mutational Mechanism in Dystrophin Gene. Genes 2017, 8, 253.

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